For centuries, various natural and unnatural compositions and/or compounds have been added to comestible (edible) foods, beverages, and/or orally administered medicinal compositions to improve their taste. Although it has long been known that there are only a few basic types of “tastes,” the biological and biochemical basis of taste perception was poorly understood, and most taste improving or taste modifying agents have been discovered largely by simple trial and error processes.
There has been significant recent progress in identifying useful derivatives of natural flavoring agents, such as for example sweeteners that are derivatives of natural saccharide sweeteners, such as for example erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol. There has also bee recent progress in identifying natural terpenoids, flavonoids, or proteins as potential sweeteners. See, for example, a recent article entitled “Noncariogenic Intense Natural Sweeteners” by Kinghorn et al. (Med Res Rev (1998)18(5):347-360), which discussed recently discovered natural materials that are much more intensely sweet than common natural sweeteners such as sucrose, fructose, glucose, and the like. Similarly, there has been recent progress in identifying and commercializing new artificial sweeteners, such as aspartame, saccharin, acesulfame-K, cyclamate, Sucralose, and alitame, etc., see an article by Ager et al. (Angew Chem Int Ed (1998) 37:1802-1817). The entire disclosures of the references identified above are hereby incorporated herein by reference, for the purpose of describing at least in part the knowledge of those of ordinary skill in the art regarding known sweetening agents.
Nevertheless, there remains in the art a need for new and improved flavoring agents and/or sweeteners. Discovery of new “High Intensity” sweeteners (i.e., many times sweeter than sucrose) would be of considerable value, especially if the new compounds induce the perception of sweetness when used at extremely low concentrations. Similarly any compounds that, when used at very low concentrations significantly multiply (enhance) the sweetness of known natural or artificial sweeteners, so that less of the known caloric sweeteners would be required, while maintaining or amplifying the perceived taste of the natural sweeteners, could be of very high utility and value in view of the rapidly increasing incidence of undesirable human weight gain and/or associated diseases such as diabetes, atherosclerosis, etc.
In recent years substantial progress has been made in biotechnology in general and in better understanding the underlying biological and biochemical phenomena of taste perception. For example, taste receptor proteins have been recently identified in mammals that are involved in taste perception. Particularly, two different families of G protein coupled receptors believed to be involved in taste perception, T2Rs and T1Rs, have been identified. (See, e.g., Nelson et al., Cell (2001) 106(3):381-390; Adler et al., Cell (2000) 100(6):693-702; Chandrashekar et al., Cell (2000) 100:703-711; Matsunami et al., Number (2000) 404:601-604; Li et. al., Proc Natl Acad Sci USA (2002) 99:4962-4966; Montmayeur et al., Nature Neuroscience (2001) 4(S):492-498; U.S. Pat. No. 6,462,148; and PCT publications WO 02/06254, WO 00/63166 art, WO 02/064631, and WO 03/001876, and U.S. Patent Publication US 2003-0232407 A1). The entire disclosures of the articles, patent applications, and issued patents cited immediately above are hereby incorporated herein by reference, for all purposes, including their disclosures of the identities and structures of T2Rs and T1Rs mammalian taste receptor proteins and methods for artificially expressing those receptors in cell lines and using the resulting cell lines for screening compounds as potential “savory” or “sweet” flavoring agents.
Whereas the T2R family includes over 25 genes that are involved in bitter taste perception, the T1R family only includes three members, T1R1, T1R2 and T1R3. (See Li et al., Proc Natl Acad Sci USA (2002) 99:4962-4966.) Recently, it was disclosed in WO 02/064631 and/or WO 03/001876 that certain T1R members, when co-expressed in suitable mammalian cell lines, assemble to form functional taste receptors. It was found that co-expression of T1R2 and T1R3 in a suitable host cell results in a functional T1R2/T1R3 “sweet” taste receptor that responds to different taste stimuli including naturally occurring and artificial sweeteners. (See Li et al., Proc Natl Acad Sci USA (2002) 99:4962-4966.) The references cited above also disclosed assays and/or high throughput screens that measure T1R1/T1R3 or T1R2/T1R3 receptor activity by fluorometric imaging in the presence of the target compounds.
It was recently reported in U.S. Patent Publication No. US 2005/0084506 A1, and in PCT Publication No. WO 2005041684, that various amide compounds can, at very low concentrations of a few micromolar or less, serve as savory and/or sweet flavoring agents, and/or savory and/or sweet flavor enhancers. The entire texts of US 2005/0084506 A1 and WO 2005041684 are hereby incorporated herein by reference, for all purposes, including the purpose of their descriptions of particular genera and subgenera of amide compounds with activity as sweet flavoring agents and/or sweet flavor enhancers.
Disclosed herein are a new class of bis-aromatic amide compounds, which because of their particular structures, serve at unexpectedly low concentrations as unexpectedly superior and/or high intensity sweet flavorant or sweet enhancing compounds in comestible compositions. These compounds are particularly valuable when used as high intensity sweeteners in combination with other known but less potent sweeteners, such as for example saccharide sweeteners, so as to allow for the formulation of comestible compositions comprising lower levels of the previously known sweeteners.